Method of producing dialkoxy stilbenes



V Patented Apr. 4,1944

UNITED STAT-E PATENT OFFICE.

2,346,042; METHOD or rnonncme nmmoxr s'mm:

NES

Ewald Rohrmann, Indianapolis, Ind, assignor to Eli Lillyand Company,Indianapolis, Ind., a corporation of Indiana No Drawing. ApplicationFebruary 13, 19 41, Serial No. 378,77 5

12 Claims. (GLEN-$13) ing this activity have been found to havesubstantially more estrogenic activity than the cis.

forms. For example, the trans, form of 4:4-

dihydroxy-azp-diethyl stilbene. known as stil-' besterol, has about tentimes the activity of the cis form of t:4'-dihydroxy-a:e-diethylstilbene. In the preparation of these estrogenically active stilbenessynthetically, approximately equal quantities of the trans and "015forms are produced and various methods have been proposed for separatingthe trans from the cis form. The methods now in use for this separationutilize difierences in physical properties between the trans and thecis" form. These methods, however, involve considerable manipulation andpro duce but. fair yields. J I

In accordance with this invention the trans" form of the dialkoxyderivative of the desired stilbene is produced in good yields. Thesedialkoxy stilbene derivatives can be readily converted to the desiredstilbene.

The'me'thod in accordance with this invention is as follows: H

Boron trichloride or boron trifluoride, or reactive complexes of borontrichloride or boron triiluoride, are reacted with a composition whichis dissolved in a solvent and which is represented by the followingformula:

in which R is a radical selected from'the class consisting of alkylradicals, alkaryl radicals, acyl radicals, aracyl radicals, andsubstituted aracyl radicals in which the substituent is selected fromthe class consisting of the halogens and nitro I themselves.

alkyl radicals containing at least one alkoxy.

group.

Preferably the composition, the structure of which is shown in Formula1, is reacted with boron trifiuoride or the reactive complex of borontrifluoride and, desirably, the reactive complexes of the halides areused instead of the halides When 'a-reactive complex is used,

Y the solvent for the composition is not essential,

although it ispreferred to have such a solvent. Examples of solventswhich may be used for this purpose are benzene, toluene, xylene, carbontetrachloride, chloroform, diethyl-ether, di-isopropyl ether, di-n-butylether, and 0-, p-, or m-methylcyclohexane. The solvent used may be onethat is inert to the boron halide or one that does not react with theboron halide to decompose that halide. The reactive complexes are formedfrom the respective halides with an organic compound and these reactivecomplexes react like the halide from which they are derived. Examples oforganic compounds which may be reacted with either boron trichloride orboron trifluoride to produce reactive complexes which react like groups;R1 is a radical selected from the class consisting of alkyl radicals,alkaryl radicals, acyl radicals, aracyl radicals, and substituted aracylradicals in which the substituent is selected from the classconsisting'of thehalogens and nitro' groups; R: is a membeh'selected,from the class consisting of alkyl radicals, aryl radicals, alkarylradicals, cycloalkyl radicals, and substituted alkyl. aryl, alkaryl, andcycloalkyl radicals containin at least one alkoxy group; and, R3 is amember selectedfrom the class consisting of alkyl radicals,

aryl radicals, alkaryl radicals, cycloalkyl radicals, and substitutedalkyl, aryl, alkaryl, and cyclothe halide from which they are derivedare:

liquid alkyl ethers, such as diethyl ether, di-

isopropyl ether, and di-n-propyl ether; liquid alkyl monocarboxylicacid, such as acetic acid, propionic acid, and butyricacid; ethylene andmethanol.

The reaction between the composition shown in\Formula 1 and the borontrichloride or boron trifluoride or the reactive complexes of either ofthese halides is maintained between 10 C. and

C. and'preterably between 10 C. and 30 C. 'Desirably, the quantity 'ofthe boron trichloride or boron trifluoride employed may be between 50and 300 percent by weight of the composition i treated. If the reactivecomplex of either boron trichloride or boron trifiuoride is used,preferably the amount of complex employed is such that the boron halidecontent is between 50 and 300 percent by weight of the compositiontreated. The reaction which takes place may be represented by thefollowing equation:

BCI: or

or both R. and R1 are both R and R1 are alkyl radicals or acyl radicals,the number of carbon atoms of each alkyl or acyl radical does not exceedthree and, preferably, when either or alkaryl radicals, aracyl radi calsor substituted aracyl radicals, each alkaryl, aracyl, or substitutedaracyl radical is the benzyl, benzoyl, or substituted benzoyl radicalrespectively. For example, desirably, either or both R1 and R2 are themethyl, ethyl, propyl, isopropyl, acetyl, propionyl, o-chlorobenzoyl, orp-nitrobenzoyl radicals. However, either or both R, and R1 may be otheralkyl or acyl radicals, such as the n-butyl, isoamyl, decyl, or caprylradical. Likewise, either or both R. and P4 may be alkaryl, aracyl, orsubstituted aracyl radicals other than the benzyl, benzoyl, orsubstituted benzoyl radical, such as p-phenethyl mesityl CH 1phenylacetyl or p-chlorophenylpropionyl.

When either or both R: and R3 are alkyl or cycloalkyl radicals, orsubstituted alkyl or cycloalkyl radicals, each of these radicalspreferably contains less than eight carbon atoms. Examples of suchradicals are propyl, n-amyl, cyclopentyl, cyclohexyl, and4-methoxycyclohexyl.

when either or both R: and R3 are aryl or alkaryl radicals orsubstituted aryl or alkaryl radicals, each of theseradicals preferablycontains less than eight carbon atoms. Examples of such radicals arephenyl, o-tolyl, benzyl, p-chlorophenyl, m-methoxyphenyl, andp-methoxybenzyl. The period of reaction is dependent upon thetemperature of the reaction mixture. A period between two to fourteendays has been found satisfactory. When the temperature is maintained atbetween 20 and 30 C. a period of from five to seven days issatisfactory. Substantially all of the reaction product formed is in the"trans" form. The dialkoxy stilbene is separated from the reactionmixture by any suitable means, such of the "018 form to the trans formmay be represented by the following equation:

Trans form Typical examples of the methods of this invention are asfollows:

Examrrs 1.-Prei aration of the "trans form of 4:4-dimethory-a:p-diethylstilbene To a solution, maintained at approximately 10 0., of 200 g. of3:4-di-(p-methoxypl1enyl) -hexane-3-ol in 800 cc. of pure carbontetrachloride are added with shaking 800 g. of boron triiiuorideethylether reactive complex. This boron trifiuoride-ethyl ether reactivecomplex is prepared by saturating ethyl ether with boron trifluoride asadding waterto the mixture to decompose the boron halide, separating thewater containing the decomposition products of the .halide, anddisltilling the solvent from the non-water miscible ayer.

Alternately, the cis form of a dialkoxy stilbene maybe converted intothe trans" form by reacting the cis form of the dialkoxy stilbene withborontrichloride, boron trifiuoride, or a reactive complex of either ofthese halides. In this case, desirablythe quantity of the borontrichloride or boron trifluoride employed may be between 5 and 200percent by weight of the composition treated. If the reactive complex ofeither boron trichloride or boron trifluoride is used, preferably theamount of complex employed is such that the boron halide content isbetween 5 and 200 percent by weight of the composition treated. Theperiod of heating and the procedure followed are thesame as those in theformation of the dialkoxy stilbene from the composition represented inFormula 1. R, R1, R2, and R3 are preferably of low molecular weight asheretofore described for the composition represented in Formula 1. Thereaction which takes place in the conversion The reaction mixture of the3:4-di-(pmethoxyphenyl) -hexane-3-ol and boron trifluoride-ethyl ethercomplex is allowed to stand at 20-25 C. forsix' days. Water is added andthe carbon tetrachloride and ether layer, which contains the desiredproduct, is thoroughly washed with water. The carbon tetrachloride andether are distilled oil and the residual syrup which solidifies oncooling is distilled at a pressure of 0.5 mm. The desired product iscrystallized from the distillate with 1:5 acetone-petroleum ether (B. P.30-60 6.). The product, which is the trans form of4:4'-dimethoxy-a:fl-dithyl stilbene, has a melting point of 122-124 (3.,uncorrected, and may be represented by the following formula:

CzHs I (4) cmo-OmcOocin CiHs EXAMPLE 2.Preparation of the "trans form of4:4'dimethoxy-mp-diethyl stilbene By treating the carbontetrachloride-ether so-'.

lution in the filtrate as described in Example 1, a further quantity ofmaterial is obtained.

Exmtz 3.Prepardtion of the "tra1is form of 4: 4'-diacetoa:y- :p-diethylstilbene To a solution, maintained at approximately 10 0., of 10 g. of3:4-di- (p-acetoxyphenyl) -hexane-3-ol in 40 cc. of dry carbontetrachloride are added with shaking 40 g. of boron trifluoride-. ethylether reactive complex. The red colored solution is allowed to stand at20-25 C. for six days, Water is added and the carbontetrachloride etherlayer is thoroughly washed with water. The carbon tetrachloride andether are removed and the residual product is distilled at a pressure aperiod of one hour.

of 0.5 min." The desired product is crystallized from the distillatewith 1:5 acetone-petroleum ether (B. P. 30-60 C.) to give white crystalsof "trans 4:4'-diacetoxy-:p-diethyl stilbene. The

product has a melting. point of 122f-124 C. and

may be represented by the following formula:

Examrta 4.--Preparation of the "tra1is form of4:4-dibenzoylozy-a:p-diethyl stilbene To a solution, maintained atapproximately 10 C., of g. of 3:4-di-(p-benzoyloxyphenyl) -hexane-3-olin 40 cc. of dry carbon tetrachloride are added with shaking 40 g. ofboron fluoride-ethyl ether reactive complex. The red colored solution isallowed to stand at 25 C. for six days.

Water is added and the carbon tetrachloride-ether layer is thoroughlywashed with water. The carbon tetrachloride and ether are removed andthe 1 residual material is dissolved in acetone' and filtered throughdecolorizing carbon. The product is crystallized from 1:3acetone-petroleum ether (B. P. 3060 C.) to give white crystals-of trans4 4' -dibenzoyloxyp-diethyl stilbene. The

product has a melting point of 208"-2l0 C., un-

corrected, and may be represented by the following formula: K F

Exemrna 5.-'-Preparation of the trans form of 4:4 -dimetho:ry-ap-dimethyl stilbene To a solution, maintained at approirimately 10 C.,of g. of 2:3-di-(p-methoxyphenyl) -butane- '2-01 in 100 cc. of drycarbon tetrachloride are troleum ether (B. P. -60 C.). has a meltingpoint of 122-12'4 C.

'ExAMrLn 7.--Prepa'ration of the "tran? form of4:4'-dimetho:w-e:p-diethill silbene To a solution, maintained atappronimatelyio" C., of50 g. of 3:4 -'di-(p-methoxyphenyl) -hexanev 3-01in 200 cc. of pure carbon tetrachloride are added with shaking 200 g. ofboron chlorideethyl ether reactive complex which is prepared bysaturating ethyl ether with boron chloride gas. The

reaction-mixture containing the 3:4-dl-(p-methoxyphenyD-hexane-3-ol isallowed to stand at' ether (B. P. 30-60). The product has a meltingpoint of 122 -124" C.

EXAMPLE- 8.'--Preparation of the trans form of 4.4'-metho:cy-e:fl-diethyl stilbene To a solution, maintained atapproximately 10 C., of 3:4-di-(p-methoxyphenyl)-hexane-3-ol in 400 cc.of pure carbon tetrachloride are added with shaking 400 g'. of boronfluoride-isopropyl ether, which is prepared by saturating isopropylether with boron trifluoride gas. The reaction mixture containing3:4-di- (p-methoxyphenyl) hexane-3-ol is allowed to stand at 20 C. forsix days. Water isadded and thecarbon tetrachlov ride-isopropyl etherlayer is thoroughly washed with water. The solvent is distilled off andthe residual product is distilled at a pressure of 0.5

added with shaking 100 g. of boron fluoride-ethyl ether reactivecomplex. The red colored solution is allowed to stand at 2025 C. forsix'days. Water is added and the carbon tetrachlorideether layer isthoroughly washed with water. The carbon tetrachloride and ether aredistilled ofi and the residual material is distilled at a pressure of0.5 mm. The desired product is crystal-- lized from the distillate with1:5 acetone-pemm. \J'I-he trans 4:4'-dimethoxy-a:p-diethyl stilbene iscrystallized from the distillate with 1:5 acetone-petroleum ether ("3,P. 30-60 C.). The product has a melting point of 122-124 C.

Exmrw 9.Preparat ion of the "trans form of 4:4-d'i'meth0$y-e-ethyl-fl-m8th1ll stilbene To a solution, maintained atapproximately 10 C.,,of g. of 3:4-di-(p-methoxyphenyD-pentame-3 61 in200 cc. of pure carbon tetrachloride troleum ether (3.. P. 3060 C.) togive white crystals of trans 4:4-dimethoxy-a:fl-dimethyl stilbene. Theproduct has a melting point-of l28-130 C. and may be represented by thefollowing formula:

e CH: EXilltlPLE 6."-Preparati0n of'the "trans" form of 4:4dimethoxy-wfi dieth jl silbene To a solution of 25 g. of3:4-dl-(p-methoxyphenyD-hexane-3-ol in 100cc. of pure carbontetrachloride are added with shaking 100 g. of

boron fluoride ethyl ether reactive complex. The red colored solution iswarmed on the steam bath and the solventis allowed to evaporate oil overare added with shaking 200 g. of boron trifluorideethylether reactivecomplex. The reaction mixture is allowed to stand for six days at.20-259C.

-Water is added and the carbon tetrachlorideether layer is thoroughlywashed with water.

- formula:

The residual product is dissolved in cc. of carbon tetrachloride and thesolution is thoroughly washed with water.

The solvent is distilled oil and thereactibn product is distilled at apressure of 0.5 mm. The trans 4:4'-dimethoxy-:,B-diethy1 stilbene iscrystallized from the distillate with' 1:5. acetone-pe-' The carbontetrachloride and ether are distilled off and the residual product isdistilled at a pressure of 0.3mm. The product is a liquid having aboiling point of 173 -176 at 0.3 mm. pressure. The product may berepresented by the following OH: I

(1H2 Cfi;OO--.C=C OCHQ Exem t! 10.-Preparation oi the f'trans" form of 4:4 -dimethoa:y- :B-di-n-butul stilbene To a solution, maintained atapproximately 10 C., of, 25 g. of 5:6-di-(p-methoxyphenyD- dcane-5-o1 ln100 cc. of pure carbon tetrachloride are added with shaking 100 g. ofboron tzifiuoride-ethyl ether reactive complex. The reactionmixt'ure isallowed to stand for five days at 20-25;C. Water is added and the carbontetrachloride -ether layer is thoroughly washed The product with water.The carbon tetrachloride and ether are distilled off and the residualproduct is distilled at a pressure of .25 mm. The product is a liquidhaving a boiling point of 191-193 at 0.25 mm. pressure. The product maybe represented by the following formula: CH:

iii emoOt gQocm What is claimed is: 1. The method of producing adisubstituted stilbene of predominantly trans" form, which comprisessubjecting to the presence of a halide selected from the classconsisting of boron trichloride, boron trifiuoride, the reactive complexof boron trichloride, and thereactive complex of boron trifluoride, acomposition represented by the following formula:

of boron trlfiuoride, in a solvent, at a temperature between 10 .C. and100 C., a composition represented by the following formula:

H OH QHQ 1: Ra in which R in each case is a radical selected from theclass consisting of alkyl radicals, aliphatic carboxylic acyl radicals,and aracyl radicals, and R2 in each case is an alkyl radical.

3. The method of producing a disubstituted stilbene of predominantlytrans form, which comprises subjecting to the presence of a halideselected from the class consisting of boron trlchloride, borontrifluoride, the reactive complex of boron trichloride, and the reactivecomplex of boron trifiuoride, in a solvent, at a temperature between 10C. and 30 C., a composition represented by the following formula:

stilbene in the "trans form, which comprises subjecting to the presenceof a halide selected from the class consisting of boron trichloride,boron trirluoride, the reactive complex of boron trichloride, and thereactive complex of boron trifiuoride, in a solvent, a composition inthe "cis" form which is represented :by the following formula:

1k ,Rz

in which R in each case is a radical selected from the class consistingof alkyl radicals, aliphatic carboxylic acyl radicals, and aracylradicals, and R2 in each case is an alkyl radical.

6. Themethod of producing a disubstituted stilbene in the trans form,which comprises subjecting to the presence of a halide selected from theclass consisting of boron trichloride, borontrifiuoride, the reactivecomplex of boron trichloride, and the reactive complex of borontrifluoride, in a solvent, at a temperature between 10 C. and C., acomposition in the cis form which is represented by the followingformula:

GHQ

in which R in each case is a radical selected from the class consistingof alkyl radicals, aliphatic carboxylic acyl radicals, and aracylradicals, and R2 in each case is an alkyl radical.

7. The method of producing a disubstituted stilbene in the trans form,which comprises subjecting to the presence of a halide selected in whichR in each case is a radical selected from the class consisting of alkylradicals, aliphatic carboxylic acyl radicals, and aracyl radicals, and

R2 in each case is an alkyl radical.

. 8; The method of producing the trans form 01 4:4'-dimethoxy-a,3-diethyl stilbene, which comprises subjecting the cis form of4:4'-dimethoxy' p-diethyl stilbene, in a solvent, to the-presence ofboron trifluoride.

9. The method of producing 4:4'-dimethoxya, 3-diethyl stilbene inpredominantly trans'- form, which comprises subjecting3:4-di(pmethoxyphenyl) hexane-3-ol, in a, solvent; to the presence ofboron trifluoride.

10. The method stilbene in predominantly trans" form, which comprisessubjecting to the presence of a halide selected from the classconsisting of boron trichloride, baton of boron trichloride, and thereactive complex of boron trifluoride, in a solvent, a compositionrepresented by the following formula:

in which R'in each case is a radical selected of producing adisubstituted trifluoride, the reactive complex irom the classconsiatina of alk'y'l radicals, aliphatic carboxylic acyl radicals; andaracyi radicals, and Ba in each case is an alkyl radical.

11. The method of producing a disubstituted stilbene in accordance withclaim 1, in predominantly trans" form in which the boron halide contentof the halide employed is between 50 and 300 percent by weight or thecomposi tion treated.

12. The method of prcduc a dlmbstituted stiibene in the "trans" iormaccordance with claim 5, in which'the boron halide content of the halideemployed is between 5 and 200 per- 5 cent by weight of the compositiontreated.

